CN102367268B - Caspofungin analogue and use thereof - Google Patents
Caspofungin analogue and use thereof Download PDFInfo
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Abstract
The invention discloses a caspofungin analogue and a use thereof. The caspofungin analogue is a compound of which a structural formula is shown in the formula 4 or is a pharmaceutically acceptable salt of the compound, wherein R1 is selected from hydroxyl, benzyloxy, phenoxyl, substituted phenoxyl or substituted benzyloxy; and R2, R3, R4 and R5 are selected from hydrogen, C1-C6 alkyl, C1 to C6 alkyloxy, hydroxyl, benzyloxyphenyl, substituted benzyloxyphenyl, nitryl, fluorine, chlorine, bromine or iodine. The invention also discloses a preparation method and the use of the caspofungin analogue.
Description
Technical field
The present invention relates to the organic compound field, relate in particular to a kind of Caspofungin analogue or its pharmacy acceptable salt and preparation method thereof.
Background technology
1974, it is found that the echinocandin compounds has good anti-microbial activity.Hereafter, people have studied the pharmacologically active of many semisynthetic echinocandin compounds.Until calendar year 2001, Caspofungin formally obtains the approval listing of U.S. FDA, and people have obtained breakthrough progress to the research of antimycotic medicine.Caspofungin is an action site uniqueness, the medicine of wide spectrum and low toxicity, its chemical structure as shown in Equation 1:
WO94/21677, EP620232, WO96/24613, US5552521, WO97/47645, US5936062, WO02/083713, J.Org.Chem., 2007,72,2335-2343, CN101792486A, CN101648994A, WO2010008493A2, US2010168415A1, EP1785432, WO2010064219A1, the preparation method of Caspofungin analogue and Caspofungin has been described.
WO94/21677 and EP620232 are with Pneumocandin B
0Be starting raw material, with the reaction of alkyl sulfhydryl or aryl mercaptan, then obtain the sulfone intermediate through peroxidation, then react in anhydrous aprotic solvent with amine compound, the gained reaction product is separated by chromatographic process and is obtained.
WO96/24613 and US5552521 are with Pneumocandin B
0The primary amide base be reduced to amine groups, yield is 47%, then with thiophenol reaction, then obtains Caspofungin with reacting ethylenediamine.
WO97/47645, US5936062 and J.Org.Chem., 2007,72,2335-2343 have reported the B with Pneumocandin
0Two kinds of Stereoselective methods that prepare Caspofungin for starting raw material.First method is take phenyl boronate as protecting group, then with Pneumocandin B
0Amide group is reduced to corresponding amido, then obtains Caspofungin with thiophenol and reacting ethylenediamine successively; Second method is with Pneumocandin B
0Be the reaction of starting raw material and thiophenol, then through the phenyl boronate protection, then pass through PneumocandinB
0Amide group obtains Caspofungin with reacting ethylenediamine after being reduced to corresponding amido.
CN101792486A and CN 101648994A disclose the B with Pneumocandin
0Be starting raw material, with reacting ethylenediamine, then the amide group of the intermediate of gained is reduced to corresponding amido obtains Caspofungin under the condition of phenyl boronate protection;
WO02/083713, US2010168415A1, EP1785432, WO2010064219A1, WO2010064219A1 disclose preparation Pneumocandin B
0The intermediate of cyano compound, then obtain Caspofungin by hydrogen reducing.
WO2010008493A2 is with Pneumocandin B
0Be starting raw material and the reaction of 4-methoxybenzenethiol, then through the phenyl boronate protection, and under the condition of 3A molecular sieve dehydration, with Pneumocandin B
0Amide group is reduced to corresponding amido, then obtains Caspofungin with reacting ethylenediamine.
Yet with regard to productive rate, purity, stability and the three wastes, published method is not the best approach for suitability for industrialized production.The repeatedly use of preparative column chromatographic step makes the industrialization cost roll up, and produces a large amount of three wastes; Certain methods must (for example adopt the 3A molecular sieve dehydration) under strict anhydrous condition operation; Majority method all uses the cacodorous highly toxic product thiophenol of tool, and operation difficulty degree is large, infringement operator ' s health, serious environment pollution; In addition, in the existing synthetic method of part, preparation Pneumocandin B
0Inevitably cause isomer to generate during the class cyano compound, stereoselectivity and yield are not high, use simultaneously expensive metal as catalyzer, cause the industrialization cost high.Therefore, in the urgent need to further studying the method for preparing Caspofungin that is fit to suitability for industrialized production.
Summary of the invention
The present invention has aimed to provide a kind of Caspofungin analogue or its pharmacy acceptable salt.
Another order purpose of the present invention provides a kind of preparation method of Caspofungin analogue.
A further object of the present invention is to provide a kind of purposes of Caspofungin analogue.
In a first aspect of the present invention, a kind of structural formula compound or its pharmacy acceptable salt as shown in Equation 4 is provided,
R wherein
1The benzyloxy that is selected from hydroxyl or benzyloxy or phenoxy group or substituent phenoxy or replaces; R
2, R
3, R
4, R
5Be selected from alkyl, alkoxyl group, hydroxyl or the benzyl oxy phenyl of C1-C6, the benzyloxy phenyl of replacement, nitro, fluorine, chlorine, bromine, the iodine of hydrogen, C1-C6.
Preferably, R wherein
1Be selected from hydroxyl or benzyloxy or phenoxy group or substituent phenoxy; R
2, R
3, R
4, R
5Be selected from alkyl, the alkoxyl group of C1-C4, hydroxyl, bromine, the nitro of hydrogen, C1-C4.
More preferably, R wherein
1Be selected from hydroxyl; R
2, R
3, R
4, R
5Be selected from hydrogen, methyl, hydroxyl.
In another preference, described structural formula of compound is the compound shown in formula 4a, formula 4b, formula 4c, formula 4d or formula 4e:
In another preference, described structural formula of compound is the compound shown in formula 4a.
In a second aspect of the present invention, provide a kind of as shown in Equation 4 compound or the preparation method of its pharmacy acceptable salt, described method comprises step:
(a) as shown in Equation 2 compound and strong leavings group compound 5 are mixed, obtain compound as shown in Equation 3; With
(b) as shown in Equation 3 compound and hydroxy-protecting agent are mixed, then mix with borane complexes, obtain compound as shown in Equation 4;
In the step (a) of aforesaid method, R in described strong leavings group compound 5
1The benzyloxy that is selected from hydroxyl or benzyloxy or phenoxy group or substituent phenoxy or replaces; R
2, R
3, R
4, R
5Be selected from alkyl, alkoxyl group, hydroxyl or the benzyl oxy phenyl of C1-C6, the benzyloxy phenyl of replacement, nitro, fluorine, chlorine, bromine, the iodine of hydrogen, C1-C6.Preferably, R in the aromatic compound 5 of described sulfydryl replacement
1Be selected from hydroxyl or benzyloxy or phenoxy group or substituent phenoxy; R
2, R
3, R
4, R
5Be selected from alkyl, the alkoxyl group of C1-C4, hydroxyl, bromine, the nitro of hydrogen, C1-C4.More preferably, R in the aromatic compound 5 of described sulfydryl replacement
1Be selected from hydroxyl; R
2, R
3, R
4, R
5Be selected from hydrogen, methyl, hydroxyl.Best, the aromatic compound 5 of described sulfydryl replacement is selected from the 4-hydroxythiophenol.
In aforesaid method, described strong leavings group compound 5 needs to mix with acid; Described acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, methylsulfonic acid or tosic acid.
In the step (a) of aforesaid method, mixing temperature is-50 ℃ to 40 ℃: preferred temperature is-20 to-15 ℃.
In the step (b) of aforesaid method, described hydroxy-protecting agent is selected from boric acid class protective material or silane reagent.
In the step (b) of aforesaid method, described borane complexes is selected from: mixture or the BH of borane and tetrahydrofuran (THF), borane and dimethyl sulphide, borane and diphenyl sulfide, borane and benzyl thioether, borane and dioxane, borane and Isosorbide-5-Nitrae oxathiane
2The mixture of Cl and dimethyl sulphide; The mixture of preferred borane and tetrahydrofuran (THF) or borane and dimethyl sulphide.
In a third aspect of the present invention, the purposes of a kind of compound provided by the invention as above or its pharmacy acceptable salt is provided, for the preparation of structural formula compound as shown in Equation 1,
In a fourth aspect of the present invention, a kind of method of preparation formula 1 compound is provided, described method comprises step: as shown in Equation 4 compound and quadrol are mixed, obtain the compound as shown in structural formula 1.
In another preference, with as shown in Equation 4 compound be dissolved in the quadrol that is selected from following solvents and mix: methyl alcohol, ethanol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Virahol, trifluoroethanol, acetonitrile or methylene dichloride; Mixing temperature is 0 ℃ to 40 ℃: preferred 25 to 35 ℃.
In another preference, the invention provides a kind of method of preparation formula 1 compound, described method comprises step:
(a) as shown in Equation 2 compound and strong leavings group compound 5 are mixed, obtain compound as shown in Equation 3;
(b) as shown in Equation 3 compound and hydroxy-protecting agent are mixed, then mix with borane complexes, obtain compound as shown in Equation 4; With
(c) as shown in Equation 4 compound and quadrol are mixed, obtain the compound as shown in structural formula 1.
In a fifth aspect of the present invention, provide a kind of as shown in Equation 4 compound or the purposes of its pharmacy acceptable salt, for the preparation of the medicine of prevention or the disease that causes for the treatment of fungi infestation.
In a sixth aspect of the present invention, a kind of pharmaceutical composition is provided, it contains as shown in Equation 4 compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
Accordingly, the invention provides the method for preparing Caspofungin that is fit to suitability for industrialized production.
Embodiment
The contriver has found a kind of simple and easy method for preparing formula 4 compounds.The contriver is through further investigation, discoverable type 4 compounds through quadrol ammonia solutions can be easy obtain structure compound as shown in Equation 1, i.e. Caspofungin.
As used herein, chemical formula or title should comprise all optics and steric isomer, and the racemic mixture that has these isomer and mixture.
The preparation method
The invention provides a kind of preparation method of compound as shown in Equation 1, described method comprises the steps:
The first step, compound and 5 mixing of strong leavings group compound with as shown in Equation 2 obtain the compound suc as formula 3;
Further, as shown in Equation 3 compound is mixed with hydroxy-protecting agent, then mix with borane complexes, obtain formula 4 compounds, more as shown in Equation 4 compound and quadrol are mixed, obtain compound as shown in Equation 1.
Initiator formula 2 compounds in preparation method provided by the invention can prepare by method well known in the art, such as but not limited to, the United States Patent (USP) 5 that on June 4th, 1991 published, describe in 021, No. 341: cultivate Zalerion arboricolaATCC 20868 in the nutritional medium of the N.F,USP MANNITOL that is rich in the main carbon source of conduct.
Strong leavings group in the present invention is the aromatic compound 5 that sulfydryl replaces, described R
1The benzyloxy that is selected from hydroxyl or benzyloxy or phenoxy group or substituent phenoxy or replaces; R
2, R
3, R
4, R
5Be selected from alkyl, alkoxyl group, hydroxyl or the benzyl oxy phenyl of C1-C6, the benzyloxy phenyl of replacement, nitro, fluorine, chlorine, bromine, the iodine of hydrogen, C1-C6.Preferably, R
1Be selected from hydroxyl or benzyloxy or phenoxy group or substituent phenoxy; R
2, R
3, R
4, R
5Be selected from alkyl, the alkoxyl group of C1-C4, hydroxyl, bromine, the nitro of hydrogen, C1-C4.More preferably, R
1Be selected from hydroxyl; R
2, R
3, R
4, R
5Be selected from hydrogen, methyl, hydroxyl.Best, aromatic compound 5 is selected from the 4-hydroxythiophenol.
The catalyzer of the first step can be the acid of any medium tenacity, such as but not limited to, trifluoroacetic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, methylsulfonic acid or tosic acid, preferred trifluoromethanesulfonic acid.
Be in embodiment at one of the present invention, the first step reaction can with formula 2 compounds and the 4-hydroxythiophenol reaction that is dissolved in acetonitrile and trifluoroacetic acid, generate and contain the diphenyl sulfide intermediate product that hydroxyl replaces, i.e. formula 3 compounds.Reaction solution with in sodium acetate aqueous solution and after obtain stable solid intermediate.
Be in embodiment at one of the present invention, the first step reaction adds phenylo boric acid that the adjacent two hydroxyls in high tyrosine fragment are protected, and obtains borate ester intermediate 6, can obviously reduce the formation of the two diphenyl sulfide compounds 7 of impurity.Temperature of reaction also can reduce.More, when phenylo boric acid is protected adjacent hydroxyl, can use stronger acid as catalyzer, as trifluoromethanesulfonic acid.
In this step, the amount of formula 5 compounds used has determined the output of end product.During the 3-5 equivalent, output is the highest.
In a preference of the present invention, in the first step reaction, the amount of 4-hydroxythiophenol used is the 3-5 equivalent, when the optimum condition of landform sulphidisation is-15 ℃ more, the trifluoromethanesulfonic acid of the phenylo boric acid of the 4-hydroxythiophenol of 3 equivalents, 2 equivalents, 3 equivalents is dissolved in acetonitrile, and the solids yield that obtains is 90-95%.
In one embodiment of the invention, second step is that formula 3 compounds are mixed with hydroxyl protecting group in polar solvent, then mixes production 4 compounds with borane complexes.
Described reduction solvent be selected from the borane mixture be dissolved in THF or other suitable solvents in the boride of metal boride, titanium or zirconium or borane and ammonia, dimethylamine, pyridine or piperazine complex compound carry out.Reductive agent borane mixture is selected from mixture or the BH of borane and tetrahydrofuran (THF), dimethyl sulphide, diphenyl sulfide, benzyl thioether, dioxane, Isosorbide-5-Nitrae oxathiane preferably
2The mixture of Cl and dimethyl sulphide; The mixture of preferred borane and tetrahydrofuran (THF) or borane and dimethyl sulphide.The described metal boride that is dissolved in tetrahydrofuran (THF) or other suitable solvents is selected from ZrCl
4/ NaBH
4Or TiCl
4/ NaBH
4Mixture.The raw material that is not reduced into amine by this reductive agent can separate with reverse-phase chromatography.
In a preference of the present invention; first the adjacent two hydroxyls in high tyrosine fragment are protected, and used N, remaining hydroxyl and the amino of two (TMS) trifluoroacetamide (BSTFA) protection of O-; obtain the reaction solution of homogeneous phase, therefore can significantly improve reaction yield.Optimum condition is that compound 4 is in tetrahydrofuran solution, 10～68 ℃ of phenylo boric acid reactions with 1.1～3.0 equivalents, the BSTFA that adds again 3～9 equivalents, in 0～68 ℃ of reaction, the reaction solution of the homogeneous phase that obtains, then add borine, obtain formula 4 compound crude products in-30～30 ℃ of reactions, then adopt hydrochloric acid cancellation reaction, then the mode of through post thin layer chromatography and crystallization obtains the sterling of compound 1.
In one embodiment of the invention, the 3rd step be with formula 4 compounds and in polar solvent with reacting ethylenediamine, production 1 compound.
Preferably, reaction can be carried out at the temperature of 0 ℃ to 40 ℃ about 0.5-96 hour.More, reaction was at room temperature carried out 24-72 hour.
Preferably, described polar solvent is selected from methyl alcohol, ethanol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Virahol, trifluoroethanol, acetonitrile or methylene dichloride, particular methanol and ethanol.
Given embodiment of the present invention, three-step reaction transfers to pH between 4-6 with acetic acid after finishing, column chromatography purification after dilute with water, dense do or crystallization obtains dry solid Caspofungin (being formula thing 1 compound).
After reaction finishes, with acetic acid, pH is transferred between 4-6 column chromatography purification after dilute with water, dense do or crystallization obtains dry solid intermediate (being formula formula 1 compound).In a preferred embodiment of the invention, described column purification is to carry out wash-out with aqueous solutions of organic solvent on reversed-phase column, and described organic solvent is selected from methyl alcohol, acetonitrile, ethanol, Virahol etc., preferred acetonitrile.
Purposes
An important use of formula 4 compounds provided by the invention can be used as exactly intermediate and obtains Caspofungin, i.e. formula 1 compound.Be about to above-mentioned formula 3 compound quadrol ammonia solutions and obtain Caspofungin.
Simultaneously, formula 3 compounds itself also can be used for effectively treating fungi infestation, and can treat and prevention has candidiasis and the caused infection of aspergillus tubigensis, or make and be used for the treatment of or the medicine of prophylaxis against infection diseases.
Given this, the present invention can also provide a kind of pharmaceutical composition, and it comprises formula 3 compounds and pharmaceutically acceptable carrier.
As used herein, term " significant quantity " refers to be used for the treatment of the carrier of agent administration, comprises various vehicle and thinner.This term refers to like this some medicament carriers: they itself are not necessary activeconstituents, and use and there is no undue toxicity.Suitable carrier is well known to those of ordinary skill in the art.Can find discussing fully about pharmaceutically acceptable vehicle in Remington ' s Pharmaceutical Sciences (Mack Pub.Co., N.J.1991).Acceptable carrier can comprise liquid on combination of traditional Chinese medicine is learned, as water, salt solution, glycerine and ethanol.In addition, also may there be complementary material in these carriers, as disintegrating agent, wetting agent, emulsifying agent, pH buffer substance etc.
Described pharmaceutical composition can be prepared into various formulations according to the different way of administration youngster.These formulations are used in following mode: oral, spray suction, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer, as in subcutaneous, vein, muscle, intraperitoneal, sheath, in ventricle, in breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and use, each feature that discloses in specification sheets can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore except special instruction is arranged, the feature that discloses is only the general example of equalization or similar features.
Major advantage of the present invention is:
1, the invention provides a kind of new Caspofungin analogue or its pharmacy acceptable salt.
2, the invention provides a kind of new preparation Caspofungin method.
3, have that route is short, reaction conditions is gentle, aftertreatment is simple, yield obviously high than prior art, do not use the cacodorous highly toxic product reagent benzene of tool thiophenol, the good characteristics such as environmental pollution and operator's injury of having avoided, alleviate to a great extent the technological operation degree-of-difficulty factor and to equipment requirements, significantly reduced production cost.
4, the preparation method of above-mentioned new Caspofungin analogue provided by the invention formula 2 compounds that adopt fermentation to obtain are starting raw material, the synthesis step of process can obtain stable intermediate, be conducive to the quality control of intermediate and finished product, be conducive to suitability for industrialized production.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, for example refers to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, the same meaning that all specialties and scientific words and the one skilled in the art who uses in literary composition is familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Embodiment 1
Formula 2 compound preparation formula 3a compounds
Under nitrogen protection, with acetonitrile (150ml), formula 2 compounds (5.0g), phenylo boric acid (0.60g) and 4-hydroxythiophenol (1.81g), stir; be cooled to-20～-15 ℃; drip trifluoromethanesulfonic acid (1.25ml, 14.13mmol), drip and finish; in about-20～-15 ℃ of reaction 2.5h; the TLC demonstration reacts completely, and the cancellation reaction slowly adds the NaOAc aqueous solution (1.15g NaOAc is dissolved in 25ml water); finish, temperature is risen to 20 ℃ stir 2h.Have a large amount of solids to separate out, then be cooled to below 0 ℃, filter, filter cake washs three times with acetonitrile/water=(V/V) 60ml washing in 9: 1, and vacuum-drying 5h obtains sample formula 3a compound (4.76g, yield 95.2%).(annotate: yield is mass yield.)
MS(ESI)1173.6(M+H
+)，1195.6(M+Na
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.35-7.45(m，2H)，7.05-7.15(m，2H)，6.7-6.8(m，4H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.27(m，9H)，3.89(m，3H)，3.72(m，2H)，2.76(dd，1H)，2.45(dd，1H)，2.40(m，1H)，2.15-2.05(m，6H)，1.99(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.87(t，3H)，0.84，(d，3H)，0.83(d，3H)。
Embodiment 2
Formula 3a compound preparation formula 4a compound
Under nitrogen protection, with formula 3a compound (2.0g), phenylo boric acid (0.28g); tetrahydrofuran (THF) (80ml); after reflux 30mi n, be cooled to room temperature, add BSTFA (2.12ml); in stirring at room 1h; be cooled to-10～-5 ℃, drip borine dimethyl sulphide complex compound (0.8ml, 0.94%); drip and finish, 10～15 ℃ of reaction 3.5h heat up.With the HPLC monitoring, transformation efficiency is 85%.Then drip 2N hydrochloric acid (4.8ml), and add entry (160ml), then stirring at room 24h, be splined on it on preparative column after dilute with water, acetonitrile/water with 25% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with 1.5 times of its dilute with waters, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its decompression is dense dried, obtain crude product formula 4a compound.Add methyl alcohol (8ml), stir molten clearly, room temperature drips ethyl acetate (24ml), then in stirring at room 2h, lowers the temperature and filters, and drying obtains formula 4a compound (1.60g, yield 80%).
MS(ESI)1159.6(M+H
+)，1181.6(M+Na
+)；
1H-NMR(500.13MHz，CD
30D)δ7.35-7.45(m，2H)，7.05-7.15(m，2H)，6.7-6.8(m，4H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.27(m，9H)，3.89(m，3H)，3.72(m，2H)，2.76(dd，1H)，2.65(m，2H)，2.45(m，2H)，2.15-2.05(m，6H)，1.99(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.87(t，3H)，0.84，(d，3H)，0.83(d，3H)。
Embodiment 3
Formula 4a compound preparation formula 1 compound
Under nitrogen protection, formula 4a compound (1.0g) is dissolved in methyl alcohol (4.2ml), is cooled to-20～-15 ℃, drip quadrol (4.2ml), drip and be warming up to 30～35 ℃ of reaction 48h after finishing, HPLC monitoring reaction transformation efficiency is 99%.it is splashed into water (36.3ml) solution of glacial acetic acid (16.6ml), then and with one times of its dilute with water, it is splined on preparative column, acetonitrile/water with 22% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with one times of its dilute with water, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its concentrating under reduced pressure is arrived do, obtain sample formula 1 compound (0.93%, 93%), HPLC purity is 99.0%, be white solid, then it is dissolved in ethanol (3ml), 6% aqueous acetic acid (0.3ml), then drip ethyl acetate (5.3ml), stir 1h in 10 ℃, filter, drying obtains Caspofungin diacetin (formula 1 compound) (0.90g, yield 90%).
MS(ESI)：1093.6(M+H
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.12(m，2H)，6.75(m，2H)，4.97(d，1H)，4.91(d，1H)，4.66(d，1H)，4.60(dd，3.2，1H)，4.56-4.51(m，2H)，4.48(dd，1H)，4.32-4.28(m，3H)4.22(dd，1H)，4.18(d，1H)，4.08-3.96(m，3H)，3.83(m，1H)，3.76(d，1H)，3.05(t，2H)，3.02-2.76(m，4H)，2.41(dd，1H)，2.29-2.17(m，3H)2.11-1.78(m，5H)，1.90(s，6H)，1.58(m，2H)，1.53-1.19(m，15H)，1.16(d，3H)，1.13-1.00(m，2H)，0.91(m，1H)，0.87(t，3H)，0.85(degenerate d，6H)；
13C-NMR(125MHz，CD
3OD)180.7，176.7，174.6，171.1，174.0，173.3，173.2，169.4，159.1，116.7，77.8，76.1，75.5，72.5，71.8，70.6，69.8，64.8，63.3，58.9，58.8，57.6，56.7，56.5，51.6，47.5，46.4，44.5，40.9，39.5，38.8，38.5，37.4，36.2，35.1，33.4，31.7，31.6，31.4，31.3，31.1，30.84，30.81，28.5，27.5，24.8。
Embodiment 4
Formula 2 compound preparation formula 3b compounds
Under nitrogen protection; with acetonitrile (100ml), formula 2 compounds (5.0g), phenylo boric acid (0.90g) and 3-hydroxythiophenol (1.80g), stir, be cooled to-50～-45 ℃; drip trifluoroacetic acid (1.05ml); drip and finish, in about-50～-45 ℃ of reaction 2.5h, the TLC demonstration reacts completely; the cancellation reaction; slowly add the NaOAc aqueous solution (1.15g NaOAc is dissolved in 25ml water), finish, temperature is risen to 20 ℃ stir 2h.Have a large amount of solids to separate out, then be cooled to below 0 ℃, filter, filter cake washs three times with acetonitrile/water=(V/V) 60ml washing in 9: 1, and vacuum-drying 5h obtains sample formula 3b compound (4.65g, yield 93%).
MS(ESI)1173.6(M+H
+)，1195.6(M+Na
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.1-7.20(m，3H)，6.7-6.9(m，5H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.76(dd，1H)，2.45(dd，1H)，2.40(m，1H)，2.15-2.05(m，6H)，1.98(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.87(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 5
Formula 3b compound preparation formula 4b compound
Under nitrogen protection, with formula 3b compound (2.0g), phenylo boric acid (0.50g); tetrahydrofuran (THF) (100ml); after reflux 30mi n, be cooled to room temperature, add BSTFA (2.12ml); in stirring at room 1h; then temperature control-20～-15 ℃ drip the tetrahydrofuran solution (13.6ml, 1M) of tetrahydrofuran complex; drip and finish, in-20～-15 ℃ of reaction 3.5h.With the HPLC monitoring, transformation efficiency is 85%.Then drip 2N hydrochloric acid (4.8ml), and add entry (160ml), then stirring at room 24h, be splined on it on preparative column after dilute with water, acetonitrile/water with 25% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with 1.5 times of its dilute with waters, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its decompression is dense dried, obtain crude product formula 4b compound.Add methyl alcohol (8ml), stir molten clearly, room temperature drips ethyl acetate (24ml), then in stirring at room 2h, lowers the temperature and filters, and drying obtains formula 4b compound (1.60g, yield 80%).
MS(ESI)1159.6(M+H
+)，1181.6(M+Na
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.1-7.20(m，3H)，6.7-6.9(m，5H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.76(dd，1H)，2.60(m，2H)，2.43(m，2H)，2.15-2.05(m，6H)，1.98(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.87(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 6
Formula 4b compound preparation formula 1 compound
Under nitrogen protection, formula 4b compound (1.0g) is dissolved in tetrahydrofuran (THF) (6ml), is cooled to 0～5 ℃, drip quadrol (4.2ml), drip and be warming up to room temperature reaction 24h after finishing, HPLC monitoring reaction transformation efficiency is 99%.it is splashed into water (36.3ml) solution of glacial acetic acid (16.6ml), then and with one times of its dilute with water, it is splined on preparative column, acetonitrile/water with 22% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with one times of its dilute with water, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its concentrating under reduced pressure is arrived do, obtain sample formula 1 compound (0.92g, 92%), HPLC purity is 99.0%, be white solid, then it is dissolved in ethanol (3ml), 6% aqueous acetic acid (0.3ml), then drip ethyl acetate (5.3ml), stir 1h in 10 ℃, filter, drying obtains Caspofungin diacetin (formula 1 compound) (0.88g, yield 88%).
Embodiment 7
Formula 2 compound preparation formula 3c compounds
Under nitrogen protection; with acetonitrile (200ml), formula 2 compounds (5.0g), phenylo boric acid (1.50g) and 4-hydroxyl-3-methylbenzene phenyl-sulfhydrate (2.05g), stir, be cooled to below-15 ℃; slowly add methylsulfonic acid (1.36g); finish, be warmed up to about 35～40 ℃ of reaction 2.5h, the TLC demonstration reacts completely; the cancellation reaction; slowly add the NaOAc aqueous solution (1.20g NaOAc is dissolved in 20ml water), finish, temperature is risen to 20 ℃ stir 2h.Have a large amount of solids to separate out, then be cooled to below 0 ℃, filter, filter cake washs three times with acetonitrile/water=(V/V) 50ml washing in 9: 1, and vacuum-drying 5h obtains sample formula 3c compound (4.60g, yield 92%).
MS(ESI)1187.6(M+H
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.15-7.20(m，3H)，7.0-6.9(m，1H)，6.6-6.7(m，3H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.75(dd，1H)，2.45(dd，1H)，2.40(m，1H)，2.20(s，3H)，2.15-2.06(m，6H)，1.97(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.88(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 8
Formula 3c compound preparation formula 4c compound
Under nitrogen protection, with formula 3c compound (2.0g), phenylo boric acid (0.48g); tetrahydrofuran (THF) (60ml); after reflux 30mi n, be cooled to room temperature, add BSTFA (2.40ml); in stirring at room 1h; then temperature control to 15～20 ℃, drip borine dimethyl sulphide solution (1.4ml, 0.94%); drip and finish, 15～20 ℃ of reaction 3.5h of temperature control.With the HPLC monitoring, transformation efficiency is 86%.Then drip 2N hydrochloric acid (4.8ml), and add entry (160ml), then stirring at room 24h, be splined on it on preparative column after dilute with water, acetonitrile/water with 25% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with 1.5 times of its dilute with waters, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its decompression is dense dried, obtain crude product formula 4c compound.Add methyl alcohol (8ml), stir molten clearly, room temperature drips ethyl acetate (24ml), then in stirring at room 2h, lowers the temperature and filters, and drying obtains formula 4c compound (1.60g, yield 80%).
MS(ESI)1173.6(M+H
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.15-7.20(m，3H)，7.0-6.9(m，1H)，6.6-6.7(m，3H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.75(dd，1H)，2.66(m，2H)，2.42(m，2H)，2.20(s，3H)，2.15-2.06(m，6H)，1.97(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.88(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 9
Formula 4c compound preparation formula 1 compound
Under nitrogen protection, formula 4c compound (1.0g) is dissolved in ethanol (5ml), in 35～40 ℃, drips quadrol (4.5ml), drip finish after in 35～40 ℃ of reaction 24h, HPLC monitoring reaction transformation efficiency is 99%.it is splashed into water (36.3ml) solution of glacial acetic acid (16.6ml), then and with one times of its dilute with water, it is splined on preparative column, acetonitrile/water with 22% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with one times of its dilute with water, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its concentrating under reduced pressure is arrived do, obtain sample formula 1 compound (0.82g, 82%), HPLC purity is 99.0%, be white solid, then it is dissolved in ethanol (3ml), 6% aqueous acetic acid (0.3ml), then drip ethyl acetate (5.3ml), stir 1h in 10 ℃, filter, drying obtains Caspofungin diacetin (formula 1 compound) (0.70g, yield 70%).
Embodiment 10
Formula 2 compound preparation formula 3d compounds
Under nitrogen protection; with acetonitrile (20ml), formula 2 compounds (1.0g), phenylo boric acid (0.12g) and 2-hydroxythiophenol (0.35g), stir, be warming up to 35～45 ℃; drip trifluoromethanesulfonic acid (0.35ml); drip and finish, in about 35～45 ℃ of reaction 2.5h, the TLC demonstration reacts completely; the cancellation reaction; slowly add the NaOAc aqueous solution (0.23gNaOAc is dissolved in 5ml water), finish, temperature is risen to 20 ℃ stir 2h.Have a large amount of solids to separate out, then be cooled to below 0 ℃, filter, filter cake washs three times with acetonitrile/water=(V/V) 12.5ml washing in 9: 1, vacuum-drying 4h, and obtaining sample formula 3d compound weight is 0.96g.
MS(ESI)1173.6(M+H
+)，1195.6(M+Na
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.1-7.20(m，3H)，7.0-6.9(m，2H)，6.65-6.9(m，3H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.75(dd，1H)，2.45(dd，1H)，2.40(m，1H)，2.15-2.06(m，6H)，1.98(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.87(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 11
Formula 3d compound preparation formula 4d compound
Under nitrogen protection, with formula 3d compound (2.0g), phenylo boric acid (0.62g); tetrahydrofuran (THF) (80ml); after reflux 30mi n, be cooled to room temperature, add BSTFA (2.80ml); in stirring at room 1h; be cooled to below-20～-15 ℃, drip borine dimethyl sulphide solution (1.8ml, 0.94%); drip and finish, 10～15 ℃ of reaction 3.5h heat up.With the HPLC monitoring, transformation efficiency is 88%.Then drip 2N hydrochloric acid (4.8ml), and add entry (160ml), then stirring at room 24h, be splined on it on preparative column after dilute with water, acetonitrile/water with 25% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with 1.5 times of its dilute with waters, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its decompression is dense dried, obtain crude product formula 4d compound.Add methyl alcohol (8ml), stir molten clearly, room temperature drips ethyl acetate (24ml), then in stirring at room 2h, lowers the temperature and filters, and drying obtains formula 4d compound (1.70g, yield 85%).
MS(ESI)1159.6(M+H
+)，1181.6(M+Na
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.1-7.20(m，3H)，7.0-6.9(m，2H)，6.65-6.9(m，3H)，5.38(s，1H)，5.05(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.75(dd，1H)，2.63(m，1H)，2.45(m，2H)，2.15-2.06(m，6H)，1.98(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.87(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 12
Formula 4d compound preparation formula 1 compound
Under nitrogen protection, formula 4d compound (1.0g) is dissolved in ethanol (4.5ml), is cooled to-20～-15 ℃, drip quadrol (4.5ml), drip and be warming up to 0～5 ℃ of reaction 96h after finishing, HPLC monitoring reaction transformation efficiency is 98%.it is splashed into water (36.3ml) solution of glacial acetic acid (16.6ml), then and with one times of its dilute with water, it is splined on preparative column, acetonitrile/water with 22% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with one times of its dilute with water, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its concentrating under reduced pressure is arrived do, obtain sample formula 1 compound (0.89g, 89%), HPLC purity is 97.0%, be white solid, then it is dissolved in ethanol (3ml), 6% aqueous acetic acid (0.3ml), then drip ethyl acetate (7.3ml), stir 1h in 10 ℃, filter, drying obtains Caspofungin diacetin (0.82g, yield 82%).
Embodiment 13
Formula 2 compound preparation formula 3e compounds
Under nitrogen protection, with acetonitrile (30ml), formula 2 compounds (1.0g), phenylo boric acid (0.23g) and 3,4-dihydroxy-benzene thiophenol (0.42g); stir; be cooled to below-50～-45 ℃, drip trifluoromethanesulfonic acid (0.25ml), drip and finish; in about-50～-45 ℃ of ℃ of reaction 2.5h; the TLC demonstration reacts completely, and the cancellation reaction slowly adds the NaOAc aqueous solution (0.23g NaOAc is dissolved in 3.5ml water); finish, temperature is risen to 20 ℃ stir 2h.Have a large amount of solids to separate out, then be cooled to below 0 ℃, filter, filter cake washs three times with acetonitrile/water=(V/V) 12.5ml washing in 9: 1, and vacuum-drying 5h obtains sample formula 3e compound weight and is (0.82g, yield 87%).
MS(ESI)1189.6(M+H
+)；，1211.6(M+Na
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.15-7.20(m，2H)，6.6-6.75(m，4H)，6.45(m，1H)，5.38(s，1H)，5.06(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.75(dd，1H)，2.45(dd，1H)，2.40(m，1H)，2.15-2.06(m，6H)，1.98(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.88(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 14
Formula 3e compound preparation formula 4e compound
Under nitrogen protection; with formula 3e compound (2.0g), phenylo boric acid (0.62g), tetrahydrofuran (THF) (60ml); after reflux 30mi n; be cooled to room temperature, add BSTFA (2.80ml), in stirring at room 1h; be cooled to-5～0 ℃; drip borine dimethyl sulphide solution (1.7ml), drip and finish, 10 ℃ of reaction 3.5h heat up.With the HPLC monitoring, transformation efficiency is 88%.Then drip 2N hydrochloric acid (4.8ml), and add entry (160ml), then stirring at room 24h, be splined on it on preparative column after dilute with water, acetonitrile/water with 25% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with 1.5 times of its dilute with waters, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its decompression is dense dried, obtain crude product formula 4e compound.Add methyl alcohol (8ml), stir molten clearly, room temperature drips ethyl acetate (24ml), then in stirring at room 2h, lowers the temperature and filters, and drying obtains formula 4e compound (1.64g, yield 82%).
MS(ESI)1175.6(M+H
+)；，1196.6(M+Na
+)；
1H-NMR(500.13MHz，CD
3OD)δ7.15-7.20(m，2H)，6.6-6.75(m，4H)，6.45(m，1H)，5.38(s，1H)，5.06(d，1H)，4.94(d，1H)，4.57(dd，1H)，4.42-4.28(m，9H)，3.89(m，3H)，3.72(m，2H)，2.75(dd，1H)，2.64(m，2H)，2.45(m，2H)，2.40(m，1H)，2.15-2.06(m，6H)，1.98(m，1H)，1.54(m，2H)，1.30-1.20(m，15H)，1.10(d，3H)，1.10-1.08(m，2H)，0.91(t，1H)，0.85-0.88(t，3H)，0.84，(d，3H)，0.83(d，3H)；
Embodiment 15
Formula 4e compound preparation formula 1 compound
Under nitrogen protection, formula 4e compound (1.0g) is dissolved in methyl alcohol (4.5ml), is cooled to-20～-15 ℃, drip quadrol (4.5ml), drip and be warming up to room temperature reaction 72h after finishing, HPLC monitoring reaction transformation efficiency is 98%.it is splashed into water (36ml) solution of glacial acetic acid (16.6ml), then and with one times of its dilute with water, it is splined on preparative column, acetonitrile/water with 22% (0.15% acetic acid) wash-out, merge the collection liquid that is rich in product, with one times of its dilute with water, still be splined in preparative column, acetonitrile/water with 90% (0.15% acetic acid) wash-out, collect product cut, its concentrating under reduced pressure is arrived do, obtain sample formula 1 compound (0.95g, 95%), HPLC purity is 97.0%, be white solid, then it is dissolved in ethanol (3ml), 6% aqueous acetic acid (0.3ml), then drip ethyl acetate (5.3ml), stir 1h in 10 ℃, filter, drying obtains fragrant clean diacetin (formula 1 the compound) (0.90g of pool, yield 90%).
Embodiment 16
The preparation of 4a compound composition
| Composition | Quantity |
| Formula 4a compound | 42mg/ml |
| Sucrose | 30mg/ml |
| N.F,USP MANNITOL | 20mg/ml |
| Acetic acid | 1.5mg/ml |
| Sodium hydroxide | The 1N sodium hydroxide solution |
In the 25ml flask, add 0.75g sucrose, 0.5g N.F,USP MANNITOL, 17.5ml water, 0.5ml75mg/ml acetum, then add the 4a compound of 42mg/ml equivalent.Stir evenly this mixing solutions, then regulate pH value to 6 with the sodium hydroxide solution of 1N, water is regulated the volume of mixing solutions.Then adopt sterilizing filter to filter, filtrate is transferred in the Glass tubing of 10ml, and every Glass tubing loading amount is 1.75ml, then it is transferred in Freeze Drying Equipment, and it is lyophilized into white powder.
Embodiment 17
The preparation of 4b compound composition
| Composition | Quantity |
| Formula 4b compound | 42mg/ml |
| Sucrose | 30mg/ml |
| N.F,USP MANNITOL | 20mg/ml |
| Acetic acid | 1.5mg/ml |
| Sodium hydroxide | The 1N sodium hydroxide solution |
In the 25ml flask, add 0.75g sucrose, 0.5g N.F,USP MANNITOL, 17.5ml water, 0.5ml75mg/ml acetum, then add the 4b compound of 42mg/ml equivalent.Stir evenly this mixing solutions, then regulate pH value to 6 with the sodium hydroxide solution of 1N, water is regulated the volume of mixing solutions.Then adopt sterilizing filter to filter, filtrate is transferred in the Glass tubing of 10ml, and every Glass tubing loading amount is 1.75ml, then it is transferred in Freeze Drying Equipment, and it is lyophilized into white powder.
Embodiment 18
The preparation of 4c compound composition
| Composition | Quantity |
| Formula 4c compound | 42mg/ml |
| Sucrose | 30mg/ml |
| N.F,USP MANNITOL | 20mg/ml |
| Acetic acid | 1.5mg/ml |
| Sodium hydroxide | The 1N sodium hydroxide solution |
In the 25ml flask, add 0.75g sucrose, 0.5g N.F,USP MANNITOL, 17.5ml water, 0.5ml75mg/ml acetum, then add the 4c compound of 42mg/ml equivalent.Stir evenly this mixing solutions, then regulate pH value to 6 with the sodium hydroxide solution of 1N, water is regulated the volume of mixing solutions.Then adopt sterilizing filter to filter, filtrate is transferred in the Glass tubing of 10ml, and every Glass tubing loading amount is 1.75ml, then it is transferred in Freeze Drying Equipment, and it is lyophilized into white powder.
Embodiment 19
The preparation of 4d compound composition
| Composition | Quantity |
| Formula 4d compound | 42mg/ml |
| Sucrose | 30mg/ml |
| N.F,USP MANNITOL | 20mg/ml |
| Acetic acid | 1.5mg/ml |
| Sodium hydroxide | The 1N sodium hydroxide solution |
In the 25ml flask, add 0.75g sucrose, 0.5g N.F,USP MANNITOL, 17.5ml water, 0.5ml75mg/ml acetum, then add the 4d compound of 42mg/ml equivalent.Stir evenly this mixing solutions, then regulate pH value to 6 with the sodium hydroxide solution of 1N, water is regulated the volume of mixing solutions.Then adopt sterilizing filter to filter, filtrate is transferred in the Glass tubing of 10ml, and every Glass tubing loading amount is 1.75ml, then it is transferred in Freeze Drying Equipment, and it is lyophilized into white powder.
Embodiment 20
The preparation of 4e compound composition
| Composition | Quantity |
| Formula 4e compound | 42mg/ml |
| Sucrose | 30mg/ml |
| N.F,USP MANNITOL | 20mg/ml |
| Acetic acid | 1.5mg/ml |
| Sodium hydroxide | The 1N sodium hydroxide solution |
In the 25ml flask, add 0.75g sucrose, 0.5g N.F,USP MANNITOL, 17.5ml water, 0.5ml75mg/ml acetum, then add the 4e compound of 42mg/ml equivalent.Stir evenly this mixing solutions, then regulate pH value to 6 with the sodium hydroxide solution of 1N, water is regulated the volume of mixing solutions.Then adopt sterilizing filter to filter, filtrate is transferred in the Glass tubing of 10ml, and every Glass tubing loading amount is 1.75ml, then it is transferred in Freeze Drying Equipment, and it is lyophilized into white powder.
The above is only preferred embodiment of the present invention, be not to limit essence technology contents scope of the present invention, essence technology contents of the present invention is broadly to be defined in the claim scope of application, any technology entity or method that other people complete, if defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.
Claims (16)
1. structural formula compound as shown in Equation 4,
R wherein
1Be selected from hydroxyl; R
2, R
3, R
4, R
5Be selected from hydrogen, methyl, hydroxyl.
2. compound as claimed in claim 1, is characterized in that, described structural formula of compound is the compound shown in formula 4a, formula 4b, formula 4c, formula 4d or formula 4e:
3. compound as claimed in claim 2, is characterized in that, described structural formula of compound is the compound shown in formula 4a.
4. the preparation method of a compound as claimed in claim 1, is characterized in that, described method comprises step:
(a) as shown in Equation 2 compound and strong leavings group compound 5 are mixed, obtain compound as shown in Equation 3; With
(b) as shown in Equation 3 compound and hydroxy-protecting agent are mixed, then mix with borane complexes, obtain compound as shown in Equation 4;
Described R
1Be selected from hydroxyl; R
2, R
3, R
4, R
5Be selected from hydrogen, methyl, hydroxyl.
5. preparation method as claimed in claim 4, is characterized in that, the aromatic compound 5 that described sulfydryl replaces is selected from the 4-hydroxythiophenol.
6. preparation method as claimed in claim 4, is characterized in that, described strong leavings group compound 5 needs to mix with acid; Described acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, methylsulfonic acid or tosic acid.
7. preparation method as claimed in claim 4, is characterized in that, in step (a), mixing temperature is-50 ℃ to 40 ℃.
8. preparation method as claimed in claim 7, is characterized in that, in step (a), mixing temperature is-20 to-15 ℃.
9. preparation method as claimed in claim 4, is characterized in that, the hydroxy-protecting agent described in step (b) is selected from boric acid class protective material or silane reagent.
10. preparation method as claimed in claim 4, it is characterized in that, borane complexes described in step (b) is selected from: mixture or the BH of borane and tetrahydrofuran (THF), borane and dimethyl sulphide, borane and diphenyl sulfide, borane and benzyl thioether, borane and dioxane, borane and Isosorbide-5-Nitrae oxathiane
2The mixture of Cl and dimethyl sulphide.
11. preparation method as claimed in claim 10 is characterized in that, described borane complexes is selected from the mixture of borane and tetrahydrofuran (THF) or borane and dimethyl sulphide.
12. the method for preparation formula 1 compound is characterized in that, described method comprises step: as shown in Equation 4 compound and quadrol are mixed, obtain the compound as shown in structural formula 1,
R wherein
1Be selected from hydroxyl; R
2, R
3, R
4, R
5Be selected from hydrogen, methyl, hydroxyl.
13. the described preparation method as claim 12, it is characterized in that, with as shown in Equation 4 compound be dissolved in the quadrol that is selected from following solvents and mix: methyl alcohol, ethanol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Virahol, trifluoroethanol, acetonitrile or methylene dichloride.
14. the described preparation method as claim 12 is characterized in that, mixing temperature is 0 ℃ to 40 ℃.
15. the described preparation method as claim 14 is characterized in that, mixing temperature is 25 to 35 ℃.
16. the method for preparation formula 1 compound is characterized in that, described method comprises step:
(a) as shown in Equation 2 compound and strong leavings group compound 5 are mixed, obtain compound as shown in Equation 3;
(b) as shown in Equation 3 compound and hydroxy-protecting agent are mixed, then mix with borane complexes, obtain compound as shown in Equation 4; With
(c) as shown in Equation 4 compound and quadrol are mixed, obtain the compound as shown in structural formula 1;
Priority Applications (6)
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| CN201010538954XA CN102367268B (en) | 2010-11-10 | 2010-11-10 | Caspofungin analogue and use thereof |
| KR1020137014784A KR101612166B1 (en) | 2010-11-10 | 2011-11-10 | Caspofungin analog and applications thereof |
| US13/884,750 US8969513B2 (en) | 2010-11-10 | 2011-11-10 | Caspofungin analog and applications thereof |
| EP11840482.1A EP2668958B1 (en) | 2010-11-10 | 2011-11-10 | Caspofungin analog and applications thereof |
| ES11840482.1T ES2567045T3 (en) | 2010-11-10 | 2011-11-10 | Caspofungin analogue and its applications |
| PCT/CN2011/082022 WO2012062213A1 (en) | 2010-11-10 | 2011-11-10 | Caspofungin analog and applications thereof |
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| CN201010538954XA CN102367268B (en) | 2010-11-10 | 2010-11-10 | Caspofungin analogue and use thereof |
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| US (1) | US8969513B2 (en) |
| EP (1) | EP2668958B1 (en) |
| KR (1) | KR101612166B1 (en) |
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| CN112110991A (en) * | 2014-12-24 | 2020-12-22 | 上海天伟生物制药有限公司 | Composition containing nitrogen heterocyclic hexapeptide precursor and preparation method and application thereof |
| CN105218645B (en) * | 2015-10-14 | 2018-08-07 | 成都雅途生物技术有限公司 | A kind of Caspofungin impurity C of high-purity high-yield0Preparation method |
| CN109721641B (en) * | 2017-10-31 | 2021-08-03 | 鲁南制药集团股份有限公司 | Synthesis method of caspofungin |
| CN111808172B (en) * | 2019-04-12 | 2023-05-12 | 上海森辉医药有限公司 | Lung candicillin B 0 Derivatives, preparation method and application thereof |
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| US5021341A (en) | 1990-03-12 | 1991-06-04 | Merck & Co., Inc. | Antibiotic agent produced by the cultivation of Zalerion microorganism in the presence of mannitol |
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- 2011-11-10 WO PCT/CN2011/082022 patent/WO2012062213A1/en active Application Filing
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| Publication number | Publication date |
|---|---|
| US8969513B2 (en) | 2015-03-03 |
| KR20130087034A (en) | 2013-08-05 |
| ES2567045T3 (en) | 2016-04-19 |
| US20130296229A1 (en) | 2013-11-07 |
| EP2668958A1 (en) | 2013-12-04 |
| WO2012062213A1 (en) | 2012-05-18 |
| CN102367268A (en) | 2012-03-07 |
| KR101612166B1 (en) | 2016-04-12 |
| EP2668958B1 (en) | 2016-02-10 |
| EP2668958A4 (en) | 2014-10-08 |
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